Rapid Isolation of Cyclotron-Produced Gallium-68

ABSTRACT

Methods for rapid isolation of radionuclides (e.g., 68Ga) produced using a cyclotron and methods for recycling of the parent isotope (e.g., 68Zn) are disclosed. In one version of the method, a solution including a radionuclide (e.g., 68Ga) is created from a target including cations (e.g., 68Zn). The solution including the radionuclide is passed through a first column including a sorbent comprising a hydroxamate resin to adsorb the radionuclide on the sorbent, and the radionuclide is eluted off the sorbent. The cations (e.g., 68Zn) are recovered from a recovery solution that has passed through the first column by passing the recovery solution through a second column including a second sorbent comprising a cation exchange resin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. Patent Application No.62/380,183 filed Aug. 26, 2016.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

This invention was made with government support under SC0008947 awardedby the Department of Energy. The government has certain rights in theinvention.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present invention relates to labeled radiopharmaceuticals. Inparticular, the invention relates to improved methods and systems forrapid isolation of radionuclides produced using a cyclotron.

2. Description of the Related Art

Radiometals (e.g., ⁶⁴Cu, ⁸⁹Zr, ⁶⁷Ga, ⁶⁸Ga, ⁸⁶Y and ^(99m)Tc) play apivotal role in nuclear medicine as therapeutic and imaging agents forradiation therapy and labeling of biologically important macromoleculeslike proteins, peptides and antibodies.

In the recent past, a rapid increase has been noted in both clinical andpreclinical studies involving ⁶⁸Ga-labeled radiopharmaceuticals [Ref.1-5]. This increase can be attributed to the favorable physicalcharacteristics of ⁶⁸Ga (E_(βmax) 1.8 MeV, β⁺ 89%, T_(1/2)=67.7 minutes)for imaging various rapidly changing processes (proliferation,apoptosis, angiogenesis) and targets (growth hormones, myocardial andpulmonary perfusion, inflammation and infection), and to some extent, tonewer, more reliable production and labeling methods [Ref. 1-5].Gallium-68 labeled somatostatin analogs have already shown theirsuperiority over the existing agent ¹¹¹In-DTPA-octreotide throughenhanced sensitivity, specificity, accuracy and cost effectiveness forthe diagnosis of patients with neuroendocrine tumors [Ref. 1, 6-9].

The clinical promise of ⁶⁸Ga-labeled radiopharmaceuticals clearlywarrants growth of the supply of ⁶⁸Ga to meet the increasing demand invarious nuclear medicine facilities. Presently, ⁶⁸Ga can be produced bytwo different approaches, (1) solid targetry [Ref. 10,11] and (2) the⁶⁸Ge/⁶⁸Ga generator [Ref. 12]. The former requires high capital cost andexpertise and specialized cyclotron facilities that accommodate solidtargets, whereas, the latter is more broadly accessible in nuclearmedicine facilities not equipped with an on-site cyclotron. Thesimplicity and lower capital cost of the ⁶⁸Ge/⁶⁸Ga generator have madeit more popular among the nuclear medicine facilities with relativelylower number of requirements for ⁶⁸Ga labeled doses [Ref. 1, 12].However, the breakthrough of trace quantities of the long-lived ⁶⁸Geparent isotope (t_(1/2)=271 days) into the eluted ⁶⁸Ga remains a concern[Ref. 13]. Furthermore, with increasing applicability of ⁶⁸Ga-labeledradiopharmaceuticals, one can foresee a need for alternative productionmethods to meet the increasing demand especially for the relatively busynuclear medicine centers having an on-site cyclotron. There have beenprevious attempts to produce ⁶⁸Ga using a cyclotron, initially employinga solid target method using ⁶⁸Zn electrodeposition on a copper substrate[Ref. 10, 14] and more recently using a solution target containing anenriched ⁶⁸ZnCl₂ solution [Ref. 15]. The solid target methods require alengthy separation step, which is not optimal for short-lived isotopeslike ⁶⁸Ga, as well as expensive solid target infrastructure.

The production of ⁶⁸Ga from a cyclotron using a liquid target method hasbeen reported [Ref. 16]. However, due to the longer processing time, useof caustic acid HBr, use of organic solvents, and the large quantity ofeluent used, this method may not be optimal for use in routineproduction and application of ⁶⁸Ga.

Thus, there is a need in the art for improved methods and systems forrapid isolation of cyclotron produced radionuclides, such as ⁶⁸Ga.

SUMMARY OF THE INVENTION

⁶⁸Ga (T_(1/2) 67.7 min) is a positron emission tomography (PET) isotopeand is used to label peptides, proteins and small molecules fordiagnostic PET imaging. ⁶⁸Ga can be produced using a low energycyclotron employing solid or liquid target methods. The processing of⁶⁸Ga produced in a cyclotron includes separation of ⁶⁸Ga from the parentisotope ⁶⁸Zn and other isotopes (¹³N, ¹¹C, ¹⁸F)) which may be formedduring isotope production. Due to the 67.7 minute half-life of ⁶⁸Ga, itis critical to have a simple and efficient processing method in order tominimize the loss of radioactivity by decay. The present disclosureprovides a method for the separation of Gallium-68 from the parentZinc-68 that reduces processing time and requires a smaller volume offinal eluent. In one version of the invention, efficient trapping on asmall volume of hydroxamate resin facilitates the reduction of finalelution volumes to provide more concentrated solutions of Ga-68 forradiolabeling. In another version of the invention, more economicalproduction of ⁶⁸Ga from a cyclotron is achieved by efficient recyclingof the parent isotope ⁶⁸Zn using a method of recycling of ⁶⁸Zn accordingto the present disclosure.

⁶⁷Ga may be used for SPECT imaging and/or therapeutic applications. Onemethod of production of ⁶⁷Ga requires separation of ⁶⁷Ga fromnonradioactive zinc cations.

In one aspect, this disclosure provides a method for producing asolution including a radionuclide. In the method, a target solution isbombarded with protons to produce a solution including a radionuclide,wherein the radionuclide is ⁶⁸Ga. The solution including theradionuclide is passed through a column including a sorbent to adsorbthe radionuclide on the sorbent, wherein the sorbent comprises ahydroxamate resin, and the radionuclide is eluted off the sorbent.

In another aspect, the disclosure provides a method for producing asolution including a radionuclide. In the method, a target solutionincluding zinc cations is bombarded with protons to produce a solutionincluding a radionuclide. The solution including the radionuclide ispassed through a first column including a first sorbent to adsorb theradionuclide on the first sorbent, and the zinc cations are recoveredfrom a recovery solution that has passed through the first column bypassing the recovery solution through a second column including a secondsorbent comprising a cation exchange resin.

In yet another aspect, the disclosure provides a method for producing asolution including a radionuclide. In the method, a solid target isbombarded with protons to produce a solid radionuclide, wherein theradionuclide is ⁶⁸Ga. A solution including the radionuclide is createdfrom the solid radionuclide. The solution including the radionuclide isthen passed through a column including a sorbent to adsorb theradionuclide on the sorbent wherein the sorbent comprises a hydroxamateresin. The radionuclide is then eluted off the sorbent.

The foregoing and other aspects and advantages of the invention willappear from the following description. In the description, reference ismade to the accompanying drawings that form a part hereof, and in whichthere is shown by way of illustration certain embodiments of theinvention. Such embodiments do not necessarily represent the full scopeof the invention, however, and reference is made therefore to the claimsand herein for interpreting the scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of an automated system for the separation of ⁶⁸Garadioisotope from a cyclotron produced solution including ⁶⁸Ga.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present disclosure provides a method forproducing a solution including a radionuclide comprising the bombardmentof a target solution with protons to produce a solution including aradionuclide, wherein the radionuclide is ⁶⁸Ga; the passing of thesolution including the radionuclide through a column including a sorbentto adsorb the radionuclide on the sorbent; and the elution of theradionuclide off the sorbent, wherein the sorbent comprises ahydroxamate resin. In one form, the target solution may comprise⁶⁸Zn-enriched zinc nitrate. The method may further comprise the elutionof the radionuclide off the sorbent using hydrochloric acid, wherein anamount of eluent of 5 milliliters or less can be used. This method maytake 30 minutes or less.

The method may further comprise adjusting pH of the solution includingthe radionuclide before passing the solution including the radionuclidethrough the column. In one version, these adjustments of the pH maycomprise a dilution of the solution with water. The volume of water fordilution may range from 10 to 50 milliliters. In another version, theadjusting of the pH may comprise an addition of an organic or inorganicbase to the solution. In this other version, the base may form a watersoluble product with ⁶⁸Ga and ⁶⁸Zn. In one form of this other version,the base is sodium bicarbonate. The pH of the solution including theradionuclide before passing the solution including the radionuclidethrough the column may be between 5 and 7, preferably in a range of 5.5to 6.5.

In this first embodiment, at least one of the steps of the method may becompleted by an automated process using a remotely controlledradiochemistry module for processing in a hot cell as depicted inFIG. 1. The yield of the radionuclide from the solution including theradionuclide may be greater than 80% by radioactivity, or greater than85% by radioactivity, or greater than 90% by radioactivity, or greaterthan 95% by radioactivity. In another form, the hydroxamate resin maycomprise hydroxamate groups bonded to a backbone comprising a materialselected from the group consisting of silica, polymer coated silica,polyacrylate, and polystyrene. In one non-limiting form, the hydroxamateresin comprises hydroxamate groups bonded to a backbone comprising anacrylic acid/acrylamide coated silica having a diol bonded phase. Thehydroxamate resin may have a particle size in a range of 10 to 100microns, or in a range of 20 to 70 microns, or in a range of 30 to 60microns. In one non-limiting form, the hydroxamate resin has a particlesize in a range of 37 to 55 microns.

In a second embodiment, the present disclosure provides a method forproducing a solution including a radionuclide comprising the bombardmentof a target solution including zinc cations with protons to produce asolution including a radionuclide; the passing of the solution includingthe radionuclide through a first column including a first sorbent toadsorb the radionuclide on the first sorbent; and the recovery of zinccations from a recovery solution that has passed through the firstcolumn by passing the recovery solution through a second columnincluding a second sorbent comprising a cation exchange resin. In oneform, the method may comprise adjusting the pH of the recovery solutionbefore passing the recovery solution through the second column. Abeneficial pH range for the recovery solution before passing therecovery solution through the second column is a pH in a range of 3 to7, or 4 to 6, or 4.5 to 5.5.

The first sorbent may be a hydroxamate resin comprising hydroxamategroups bonded to a backbone comprising a material selected from thegroup consisting of silica, polymer coated silica, polyacrylate, andpolystyrene. In one non-limiting form, the hydroxamate resin compriseshydroxamate groups bonded to a backbone comprising an acrylicacid/acrylamide coated silica having a diol bonded phase. Thehydroxamate resin may have a particle size in a range of 10 to 100microns, or in a range of 20 to 70 microns, or in a range of 30 to 60microns. In one non-limiting form, the hydroxamate resin has a particlesize in a range of 37 to 55 microns. The second sorbent may comprise apolymeric resin having sulfonic acid groups. The second sorbent may be apolystyrene-divinylbenzene sulfonic acid such as that sold under thetradename AG® 50W-X8. The second sorbent may be a styrene-divinylbenzeneco-polymer containing iminodiacetic acid groups such as that sold underthe tradename Chelex® 100.

The method may further comprise washing the second column with deionizedwater before passing the recovery solution through the second column.The method may also comprise pushing air through the second columnbefore passing the recovery solution through the second column. In yetanother form, the target solution may comprise ⁶⁸Zn-enriched zincnitrate. The recovery of the zinc cations from the second column may be90% or greater based on weight of the zinc cations in the targetsolution, or 93% or greater based on weight of the zinc cations in thetarget solution, or 95% or greater based on weight of the zinc cationsin the target solution, or 98% or greater based on weight of the zinccations in the target solution. In this second embodiment, at least oneof the steps of the method may be completed by an automated process.

In a third embodiment, the present disclosure provides a method forproducing a solution including a radionuclide comprising the bombardmentof a solid target with protons to produce a solid radionuclide, whereinthe radionuclide is ⁶⁸Ga; the creation of a solution including theradionuclide from the solid radionuclide; the passing of the solutionincluding the radionuclide through a column including a sorbent toadsorb the radionuclide on the sorbent; and the elution of theradionuclide off the sorbent, wherein the sorbent comprises ahydroxamate resin. In one form, the target solution may comprise⁶⁸Zn-enriched zinc nitrate. The method may further comprise the elutionof the radionuclide off the sorbent using hydrochloric acid, wherein anamount of eluent of 5 milliliters or less can be used. This method maytake 30 minutes or less.

The method may further comprise adjusting pH of the solution includingthe radionuclide before passing the solution including the radionuclidethrough the column. In one version, these adjustments of the pH maycomprise a dilution of the solution with water. The volume of water fordilution may range from 10 to 50 milliliters. In another version, theadjusting of the pH may comprise an addition of an organic or inorganicbase to the solution. In this other version, the base may form a watersoluble product with ⁶⁸Ga and ⁶⁸Zn. In one form of this other version,the base is sodium bicarbonate. The pH of the solution including theradionuclide before passing the solution including the radionuclidethrough the column may be between 5 and 7, preferably in a range of 5.5to 6.5.

In this third embodiment, at least one of the steps of the method may becompleted by an automated process using a remotely controlledradiochemistry module for processing in a hot cell as depicted inFIG. 1. The yield of the radionuclide from the solution including theradionuclide may be greater than 80% by radioactivity, or greater than85% by radioactivity, or greater than 90% by radioactivity, or greaterthan 95% by radioactivity. In another form, the hydroxamate resin maycomprise hydroxamate groups bonded to a backbone comprising a materialselected from the group consisting of silica, polymer coated silica,polyacrylate, and polystyrene. In one non-limiting form, the hydroxamateresin comprises hydroxamate groups bonded to a backbone comprising anacrylic acid/acrylamide coated silica having a diol bonded phase. Thehydroxamate resin may have a particle size in a range of 10 to 100microns, or in a range of 20 to 70 microns, or in a range of 30 to 60microns. In one non-limiting form, the hydroxamate resin has a particlesize in a range of 37 to 55 microns.

EXAMPLES

The following Examples are provided in order to demonstrate and furtherillustrate certain embodiments and aspects of the present invention andare not to be construed as limiting the scope of the invention.

Example 1 Introduction to Example 1

Hydroxamate mediated separation of Ga-68 from Zn-68 reduces processingtime and provides a smaller volume of final eluent. Without limiting thepresent disclosure to a particular theory, it is contemplated thatbecause Ga³⁺ forms a hard Lewis acid in solution that it should formstable complexes with hard Lewis base groups, e.g., N, O groups ofhydroxamate. In contrast, zinc forms a borderline Lewis acid, which hasless of a chemical affinity for the hydroxamate resin. Efficienttrapping on a small volume of hydroxamate resin should also facilitatethe reduction of final elution volumes to provide more concentratedsolutions of Ga-68 for radiolabeling. Experiments were performedaccording to the following procedure.

Materials and Methods Chemicals

Zn-68 (99.23%) enriched metal was purchased from Cambridge IsotopesLaboratory (Tewksbury, Mass.). Hydrochloric acid (34-37% as HCl) andnitric acid (67-70% as HNO₃) both trace metals basis were purchased fromFisher Scientific (Suwanee, Ga.). AG-50W-X8 (polystyrene-divinylbenzenesulfonic acid resin, 200-400 mesh, hydrogen form) resin was purchasedfrom Bio-Rad (Hercules, Calif.). Accell Plus CM (300 Å, WAT 010740)cation exchange resin (acrylic acid/acrylamide coated silica having adiol bonded phase—particle size: 37-55 μm—pore size: 300 angstroms) waspurchased from Waters Inc. (Milford, Mass.). The activity readings weremeasured using a CRC dose calibrator (#416 setting, CRC-55tPET,Capintec, Ramsey, N.J.).

Synthesis of Hydroxamate Resin

Synthesis of hydroxamate resin was performed using a method developed byPandey et al. [see Ref. 17 which is hereby incorporated by reference inthe present disclosure]. Briefly, the hydroxamate resin was synthesizedby stirring Accell Plus CM resin (2.00 g), methyl chloroformate (2.0 mL,25.8 mmol) and triethylamine (2.0 mL, 14.3 mmol) in anhydrousdichloromethane (30 mL) at 0° C. for 30 minutes and then at roomtemperature for additional 90 minutes. The temperature of the mixturewas further lowered to 0° C. before addition of hydroxylaminehydrochloride (0.6 g, 8.63 mmol) and triethylamine (2.0 mL, 14.3 mmol).The resultant mixture was stirred at room temperature for an additional15 hours. The solvent was removed under vacuum, and cold water waspoured with constant stirring into the flask containing thefunctionalized resin. The resin was filtered, washed extensively withwater, and dried under vacuum.

Hydroxamate resin can also be prepared on various types of backbonepolymers/resins including but not limited to polystyrene, silica,polyacrylate, polymer coated with silica or any other organic/inorganicbackbone materials. Furthermore, the high degree of hydroxamatefunctionalization on any back bone polymer with different mesh sizes(bead size) enhances the separation of Ga-68/67 from Zn-68.

Results and Discussion Isolation of ⁶⁸Ga

A solution including ⁶⁸Ga was produced in a solution target via 30minute proton irradiation (current=20 μA) of a solution of 1.7 M⁶⁸Zn-zinc nitrate (99.23% isotopic enrichment) in 0.2 N nitric acidusing a method developed by Pandey et al. [see Ref. 16 which is herebyincorporated by reference in the present disclosure]. A column loadedwith 100 mg of the hydroxamate resin as synthesized above was pre-washedwith 1 mL of acetonitrile and 10 mL of water. After irradiation, thecontents of the cyclotron target was delivered to a collection vialpre-loaded with 25 mL of 20 mM NaHCO₃. The pH of the resultant solution(after addition of acidic target solution) was found to be in the range5.5-6.5 for effective trapping of ⁶⁸Ga on the hydroxamate resin. Theneutralized target solution was passed through the hydroxamate resin totrap ⁶⁸Ga, while allowing ⁶⁸Zn and shorter lived isotopes ¹³N, ¹¹C topass through. Further rinsing of the parent ⁶⁸Zn from the column wasperformed using 50 mL of water (pH 5.5). All ⁶⁸Zn containing fractionswere collected in a recovery vial for recycling of the parent ⁶⁸Znisotope. Finally, ⁶⁸Ga was eluted from the hydroxamate resin with 2 mL 2M hydrochloric acid and collected in a product vial for subsequentlabeling.

This process was automated using a remotely controlled radiochemistrymodule for processing in a hot cell as depicted in FIG. 1. Aprogrammable microprocessor-based controller was in electricalcommunication with valves V of the system 100 of FIG. 1 to open andclose the valves when necessary to transfer fluids in the fluid lines Lof FIG. 1. Suitable timing of valve opening and closing was programmedin the controller. The processing was achieved in approximately 20minutes with greater than 80% yield, decay corrected to start ofprocessing.

Using the radiochemistry module as depicted in FIG. 1 with thehydroxamate resin as synthesized above, processing times of 20-25minutes can provide a trapping efficiency of 70-90%, an elutionefficiency of 95-98%, and an overall efficiency of 70-90%.

An analysis of metal impurities in the ⁶⁸Ga product was as follows: Ga:0.3±0.1 μg, Cu: 10.2±7.3 μg, Zn: 33.3±21 μg, and Fe: 31.9±26.2 μg for anICP-MS analysis of ten different batches.

Recycling of ⁶⁸Zn

Economical production of ⁶⁸Ga from a cyclotron requires efficientrecycling of the parent isotope ⁶⁸Zn. A method of recycling of ⁶⁸Zn wasalso developed. The pH of the recovered ⁶⁸Zn solution (above) wasadjusted to pH=5.0 by addition of nitric acid. The resultant ⁶⁸Znsolution was passed through a column containing 1.5 grams of cationexchange resin (Bio-Rad AG-50W-X8, 200-400 mesh, hydrogen form). Priorto use, the cation exchange resin was washed with 60 mL of waterfollowed by 20 mL of air. ⁶⁸Zn was trapped on the cation exchange resin.The resin was washed with an additional 10-15 mL of water (pH 5.0-5.5)with minimal loss of ⁶⁸Zn. Finally, ⁶⁸Zn was eluted from the resin with15 mL of 8 M HNO₃. The recovered ⁶⁸Zn nitrate solution was dried undervacuum for subsequent use to produce ⁶⁸Ga. ⁶⁸Zn recovery was found toexceed 98%. ICP-MS analysis of the recovered ⁶⁸Zn showed presence ofinsignificant quantities of metal ion impurities, such as sodium.

Thus, an improved method of Ga-68 purification and ⁶⁸Zn recovery havebeen achieved. The developed method further simplifies a solution targetapproach of ⁶⁸Ga production.

Example 2

Hydroxamate mediated separation of ⁶⁸Ga from ⁶⁸Zn is facilitated by a pHadjustment of the target solution. As will be detailed below, theseparation of ⁶⁸Ga from ⁶⁸Zn has been accomplished in two differentways.

Non-Base Mediated pH Adjustment

First, a non-base mediated pH adjustment was performed through dilutionof post-irradiated ⁶⁸Ga target solution with water. Various quantitiesof water were used to achieve different pH values before trapping ⁶⁸Gaon hydroxamate resin. The amount of water used to adjust pH increaseswith increasing strength of the nitric acid and/or molarity of the ⁶⁸Znsolutions used in target irradiation. Results are shown below in Table1.

TABLE 1 Summary of the Non-Base Mediated Purification of Ga-68 from theZn-68 Run # 1 2 3 4 5 Solution 0.5M salt in 0.8N HNO₃ compositionIrradiation 45 μA, 30 min 45 μA, 60 min condition Hydroxamate 700 mg 700mg 250 mg 250 mg 750 mg (mg) (modified) Amount of 15.0 mL water used(mL) Turbidity/ No No No No No precipitate % of activity  9.5% 18.9%14.2%  9.6% 23.1% as Product % of activity 88.5% 76.9% 84.3% 88.3% 63.4%in Zn-68 recovery vial % of activity  2.0%  4.1%  1.3%  2.1% 13.5%retained on hydroxamate

Base Mediated pH Adjustment

Various organic and inorganic bases were employed to achieve a desiredpH of the target solution before trapping ⁶⁸Ga on hydroxamate resin.Herein, we demonstrated the use of sodium bicarbonate to achieve thedesired pH. The amount of base (bicarbonate or appropriateorganic/inorganic base) used to adjust pH is dependent upon the strengthof the nitric acid and molarity of the ⁶⁸Zn solutions used in targetirradiation. Higher concentrations of nitric acid and ⁶⁸Zn nitrate saltrequired higher strength of base solution to adjust the pH to thedesired level (pH between 5.5 and 6.5). The selection of base alsodepends upon the solubility of the resultant species formed afterneutralization. If the resultant species formed are insoluble in aqueoussolution, then they cannot be used for automated separation of ⁶⁸Ga fromparent ⁶⁸Zn. For example, if the acidic post-irradiation target solutionis neutralized with sodium hydroxide, then the resultant species formedwill be zinc hydroxide and gallium hydroxide. The hydroxides of Ga andZn are poorly soluble in water and therefore, would not be appropriate.Similar rationale can be applied to other organic/inorganic bases beforetheir use in this hydroxamate based method of separation of ⁶⁸Ga from⁶⁸Zn. Sodium bicarbonate was chosen because it yields sodium nitrate,carbonic acid and zinc bicarbonate after neutralization and allows ⁶⁸Znnitrate to be obtained effectively during the recycling process. Resultsare shown below in Table 2.

TABLE 2 Summary of the Base Mediated Purification of Ga-68 from theZn-68 Run # 1 2 3 4 5 6 7 8 9 Solution 0.5M salt in 1.0M salt in 0.8NHNO₃ 1.0M salt 1.0M salt in 1.5N HNO₃ composition 0.8N HNO₃ in 1.25NHNO3 Irradiation 30 μA, 40 μA 20 μA, 30 μA, 40 μA, 30 μA, 40 μA 30 μA,60 min condition 60 min 60 min 60 min 60 min 60 min 60 min 60 minHydroxamate 100 mg (mg) (modified) pH (after 6.0 5.86 5.96 6 5.9 5.925.96 5.94 5.95 neutralization) O•13N NaHCO₃ 14.3 12.9 21.0 25.4 25.4(mL) Turbidity/ No No No No No No No no no precipitate % of activity as69.34 68.53 82.49 86.10 71.26 89.80 73.94 76.18 80.49 Product % ofactivity in 28.50 29.21 13.65 10.07 27.26 7.83 19.82 21.88 5.06 Zn-68recovery vial % of activity 2.16 2.26 3.86 3.83 1.48 2.37 6.25 1.9414.44 retained on hydroxamate Note: 1. Activity lost in the lines andcollection flask have not been included in the calculation. 2. Theseruns are processed after 2.5 to 3 hours post irradiation.

Recycling of ⁶⁸Zn

Recycling of recovered ⁶⁸Zn(NO₃)₂ was performed on a cation exchangecolumn using 1.5-1.6 grams of AG 50W-X8 resin. Prior to the recycling of⁶⁸Zn, an AG 50W-X8 resin column was washed with 60 mL of deionized waterdropwise followed by 20 mL of air. Before passing the recovery solutionthrough the column, the pH of the recycling solution was adjusted to ≤5using dilute nitric acid, if needed. After passing the recovery solutionthrough the column, 20 mL of air was also pushed through. The column waswashed with 10 mL of deionized water, followed by 20 mL of air. ⁶⁸Zn waseluted with 15 mL of 8N HNO₃ into a fresh vial, and followed by 20 mL ofair. The obtained ⁶⁸Zn nitrate solution was concentrated on a rotaryevaporator. The column was regenerated by passing an additional 2 mL ofconcentrated HNO₃ (15.9 N). To reuse this column, a step of activationwith 60 mL of deionized water and a step of 20 mL of air were performed.Results are shown below in Tables 3-4.

TABLE 3 % of Zn-68 nitrate recovered in comparison with known startingmass of zinc nitrate (Batch-1) Mass of Zinc Mass Found Nitrate AfterRecycling Molarity of Hexahydrate Concentration process Solution (M)Used (g) (g) Efficiency 1 0.5 0.330 0.293 2 0.5 0.330 0.354 3 0.5 0.3300.403 4 1 0.660 0.571 5 1 0.660 0.531 Total 2.310 2.152 93.2%

TABLE 4 % of Zn-68 nitrate recovered in comparison with known startingmass of zinc nitrate (Batch-2). Mass of Zinc Mass Found Nitrate AfterRecycling Molarity of Hexahydrate Concentration process Solution (M)Used (g) (g) Efficiency 1 1 0.660 0.629 2 1 0.660 0.737 3 1 0.660 0.4704 1 0.660 0.590 Total 2.640 2.426 91.9%

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The citation of any document or reference is not to be construed as anadmission that it is prior art with respect to the present invention.

Thus, the present invention provides improved methods and systems forrapid isolation of cyclotron produced radionuclides, such as ⁶⁸Ga. Themethods of processing ⁶⁸Ga and recycling of ⁶⁸Zn offer an economicalalternative to ⁶⁸Ge/⁶⁸Ga generators.

Although the invention has been described with reference to certainembodiments, one skilled in the art will appreciate that the presentinvention can be practiced by other than the described embodiments,which have been presented for purposes of illustration and not oflimitation. Therefore, the scope of the appended claims should not belimited to the description of the embodiments contained herein.

What is claimed is:
 1. A method for producing a solution including aradionuclide, the method comprising: (a) bombarding a target solutionwith protons to produce a solution including a radionuclide, wherein theradionuclide is ⁶⁸Ga; (b) passing the solution including theradionuclide through a column including a sorbent to adsorb theradionuclide on the sorbent; and (c) eluting the radionuclide off thesorbent, wherein the sorbent comprises a hydroxamate resin.
 2. Themethod of claim 1, wherein the target solution comprises ⁶⁸Zn-enrichedzinc nitrate.
 3. The method of claim 1, wherein step (c) compriseseluting the radionuclide off the sorbent using hydrochloric acid.
 4. Themethod of claim 1, wherein step (c) comprises eluting the radionuclideoff the sorbent with an amount of eluent of 5 milliliters or less. 5.The method of claim 1, wherein the method takes 30 minutes or less. 6.The method of claim 1, wherein step (b) comprises adjusting pH of thesolution including the radionuclide before passing the solutionincluding the radionuclide through the column.
 7. The method of claim 6,wherein the adjusting of the pH comprises a dilution with water.
 8. Themethod of claim 6, wherein the adjusting of the pH comprises an additionof a base.
 9. The method of claim 8, wherein the base forms a solubleproduct with ⁶⁸Ga and ⁶⁸Zn.
 10. The method of claim 8, wherein the baseis sodium bicarbonate.
 11. The method of claim 1, wherein pH of thesolution including the radionuclide before passing the solutionincluding the radionuclide through the column is between 5 and
 7. 12.The method of claim 1, wherein at least one of step (a), step (b), andstep (c) are completed by an automated process.
 13. The method of claim1, wherein yield of the radionuclide from the solution including theradionuclide is greater than 80% by radioactivity.
 14. The method ofclaim 1, wherein the hydroxamate resin comprises hydroxamate groupsbonded to a backbone comprising a material selected from the groupconsisting of silica, polymer coated silica, polyacrylate, andpolystyrene.
 15. The method of claim 1, wherein the hydroxamate resincomprises hydroxamate groups bonded to a backbone comprising an acrylicacid/acrylamide coated silica having a diol bonded phase.
 16. The methodof claim 1, wherein the hydroxamate resin has a particle size in a rangeof 10 to 100 microns.
 17. A method for producing a solution including aradionuclide, the method comprising: (a) bombarding a target solutionincluding zinc cations with protons to produce a solution including aradionuclide; (b) passing the solution including the radionuclidethrough a first column including a first sorbent to adsorb theradionuclide on the first sorbent; and (c) recovering zinc cations froma recovery solution that has passed through the first column using asecond column including a second sorbent, the second sorbent comprisinga cation exchange resin.
 18. The method of claim 17, wherein step (c)comprises adjusting the pH of the recovery solution before passing therecovery solution through the second column.
 19. The method of claim 17,wherein the second sorbent comprises a resin having sulfonic acidgroups.
 20. The method of claim 19, wherein the second sorbent ispolystyrene-divinylbenzene sulfonic acid.
 21. The method of claim 17,wherein step (b) further comprises washing the second column withdeionized water before passing the recovery solution through the secondcolumn.
 22. The method of claim 21, wherein step (b) further comprisespushing air through the second column before passing the recoverysolution through the second column.
 23. The method of claim 17, whereinthe target solution comprises ⁶⁸Zn-enriched zinc nitrate.
 24. The methodof claim 17, wherein the recovery of the zinc cations in step (c) is 90%or greater based on weight of the zinc cations in the target solution.25. The method of claim 17, wherein the first sorbent comprises ahydroxamate resin comprising hydroxamate groups bonded to a backbonecomprising a material selected from the group consisting of silica,polymer coated silica, polyacrylate, and polystyrene.
 26. The method ofclaim 25, wherein the hydroxamate resin comprises hydroxamate groupsbonded to a backbone comprising an acrylic acid/acrylamide coated silicahaving a diol bonded phase.
 27. The method of claim 25, wherein thehydroxamate resin has a particle size in a range of 10 to 100 microns.28. The method of claim 17, wherein at least one of step (a), step (b),and step (c) are completed by an automated process.
 29. A method forproducing a solution including a radionuclide, the method comprising:(a) bombarding a solid target with protons to produce a solidradionuclide, wherein the radionuclide is ⁶⁸Ga; (b) creating a solutionincluding the radionuclide from the solid radionuclide; (c) passing thesolution including the radionuclide through a column including a sorbentto adsorb the radionuclide on the sorbent; and (d) eluting theradionuclide off the sorbent, wherein the sorbent comprises ahydroxamate resin.
 30. The method of claim 29, wherein the solutioncomprises ⁶⁸Zn-enriched zinc nitrate.
 31. The method of claim 29,wherein step (c) comprises eluting the radionuclide off the sorbentusing hydrochloric acid.
 32. The method of claim 29, wherein step (c)comprises eluting the radionuclide off the sorbent with an amount ofeluent of 5 milliliters or less.
 33. The method of claim 29, wherein themethod takes 30 minutes or less.
 34. The method of claim 29, whereinstep (b) comprises adjusting pH of the solution including theradionuclide before passing the solution including the radionuclidethrough the column.
 35. The method of claim 34, wherein the adjusting ofthe pH comprises a dilution.
 36. The method of claim 34, wherein theadjusting of the pH comprises an addition of a base.
 37. The method ofclaim 36, wherein the base forms a soluble product with ⁶⁸Ga and ⁶⁸Zn.38. The method of claim 36, wherein the base is sodium bicarbonate. 39.The method of claim 29, wherein pH of the solution including theradionuclide before passing the solution including the radionuclidethrough the column is between 5 and
 7. 40. The method of claim 29,wherein at least one of step (a), step (b), and step (c) are completedby an automated process.
 41. The method of claim 29, wherein yield ofthe radionuclide from the solution including the radionuclide is greaterthan 80%.
 42. The method of claim 29, wherein the hydroxamate resincomprises hydroxamate groups bonded to a backbone comprising a materialselected from the group consisting of silica, polymer coated silica,polyacrylate, and polystyrene.
 43. The method of claim 29, wherein thehydroxamate resin comprises hydroxamate groups bonded to a backbonecomprising an acrylic acid/acrylamide coated silica having a diol bondedphase.
 44. The method of claim 29, wherein the hydroxamate resin has aparticle size in a range of 10 to 100 microns.